CN111905094A - Ophthalmic composition and application thereof in preparation of medicine for treating xerophthalmia - Google Patents
Ophthalmic composition and application thereof in preparation of medicine for treating xerophthalmia Download PDFInfo
- Publication number
- CN111905094A CN111905094A CN202010544698.9A CN202010544698A CN111905094A CN 111905094 A CN111905094 A CN 111905094A CN 202010544698 A CN202010544698 A CN 202010544698A CN 111905094 A CN111905094 A CN 111905094A
- Authority
- CN
- China
- Prior art keywords
- ectoin
- cyclosporine
- medicament
- preparation
- eye
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 title claims abstract description 16
- 208000005494 xerophthalmia Diseases 0.000 title abstract description 20
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims abstract description 63
- 108010036949 Cyclosporine Proteins 0.000 claims abstract description 58
- 229960001265 ciclosporin Drugs 0.000 claims abstract description 58
- WQXNXVUDBPYKBA-YFKPBYRVSA-N ectoine Chemical compound CC1=[NH+][C@H](C([O-])=O)CCN1 WQXNXVUDBPYKBA-YFKPBYRVSA-N 0.000 claims abstract description 58
- 229930182912 cyclosporin Natural products 0.000 claims abstract description 54
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 23
- 239000000661 sodium alginate Substances 0.000 claims description 23
- 235000010413 sodium alginate Nutrition 0.000 claims description 23
- 229940005550 sodium alginate Drugs 0.000 claims description 23
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 claims description 23
- 229960004224 tyloxapol Drugs 0.000 claims description 23
- 229920001664 tyloxapol Polymers 0.000 claims description 23
- 239000008215 water for injection Substances 0.000 claims description 23
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 18
- 229930105110 Cyclosporin A Natural products 0.000 claims description 16
- 206010013774 Dry eye Diseases 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- -1 methyl ectoine Chemical compound 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 6
- WQXNXVUDBPYKBA-UHFFFAOYSA-N Ectoine Natural products CC1=NCCC(C(O)=O)N1 WQXNXVUDBPYKBA-UHFFFAOYSA-N 0.000 claims description 5
- 229960004063 propylene glycol Drugs 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 24
- 229940079593 drug Drugs 0.000 abstract description 10
- 206010067484 Adverse reaction Diseases 0.000 abstract description 7
- 230000006838 adverse reaction Effects 0.000 abstract description 7
- 238000012360 testing method Methods 0.000 description 21
- 239000003889 eye drop Substances 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 15
- 229940012356 eye drops Drugs 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 239000000825 pharmaceutical preparation Substances 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000007794 irritation Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 230000001954 sterilising effect Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 206010006784 Burning sensation Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 208000003251 Pruritus Diseases 0.000 description 4
- 238000009455 aseptic packaging Methods 0.000 description 4
- 230000003796 beauty Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 210000004087 cornea Anatomy 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 229920000742 Cotton Polymers 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010015958 Eye pain Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000283977 Oryctolagus Species 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 230000007928 solubilization Effects 0.000 description 3
- 238000005063 solubilization Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 2
- 206010015946 Eye irritation Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 206010048222 Xerosis Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 231100000013 eye irritation Toxicity 0.000 description 2
- 210000000744 eyelid Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 230000007803 itching Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 231100000286 mucous membrane, eye irritation or corrosion testing Toxicity 0.000 description 2
- 229940023490 ophthalmic product Drugs 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 206010027146 Melanoderma Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 206010034960 Photophobia Diseases 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003732 agents acting on the eye Substances 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 208000003464 asthenopia Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 230000004453 corneal transparency Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 229940020947 fluorescein sodium Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 231100001032 irritation of the eye Toxicity 0.000 description 1
- 210000004561 lacrimal apparatus Anatomy 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 210000001232 limbus corneae Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940053174 restasis Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 230000007279 water homeostasis Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Ophthalmology & Optometry (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses an ophthalmic composition and application thereof in preparing a medicine for xerophthalmia, and belongs to the technical field of medicinal preparations. The invention combines the ectoin or the derivative thereof and the cyclosporine, thereby not only improving the treatment effect on the xerophthalmia, but also effectively reducing the side effect and the adverse reaction of a xerophthalmia treatment product which independently takes the cyclosporine as the effective component, and improving the use comfort and the medication compliance of patients.
Description
Technical Field
The application relates to the technical field of medicines, in particular to an ophthalmic medicine composition containing ectoin or derivatives thereof and application thereof in preparing medicines for treating xerophthalmia.
Background
Xerophthalmia (dyreyesyndrome, xeorphhtalmia), also known as keratoconjunctival xerosis, is a common ophthalmic disease which is frequently seen in women of 40-50 years old and is caused by lacrimal gland hyposecretion caused by various factors of eyes and/or the whole body (such as ocular surface dysfunction, ocular trauma, diabetes, inflammation and the like) to cause lacrimal film abnormality and ocular surface epithelial xerosis. Clinical initial manifestations of dry eye patients include foreign body sensation, dryness, itching, burning, photophobia, blurred vision, asthenopia, unsightly discomfort, and inability to tolerate environments with smoke. These symptoms worsen as the disease progresses, eventually leading to corneal ulceration and even blindness.
The main existing treatment methods for the xerophthalmia include drug treatment and surgical treatment. Among them, the drug therapy mainly includes tear substitutes, drugs for stimulating tear secretion and therapeutic drugs for etiology.
Cyclosporine is a new type of powerful immunosuppressant, features high efficiency and low toxicity, and can inhibit the proliferation of T lymphocyte and B lymphocyte, influence immune system selectively and realize the inhibition of immune system. In addition, cyclosporin has various physiological activities such as anti-inflammation, anti-infection, antifungal, etc. The product of applying cyclosporine to dry eye treatment is liyanda (Restasis, 0.05% cyclosporine), is the first medicine for treating dry eye from pathogenesis in the world, and relieves the ocular inflammatory reaction of dry eye patients through anti-inflammatory action, thereby achieving the effect of treating dry eye. However, the eye beauty has many side effects, the most common side effect is eye burning sensation, and the incidence rate reaches 17%; in addition, there are adverse effects with an incidence of 1% to 5%, including conjunctival congestion, secretions, watery eyes, eye pain, foreign body sensation, itching, stinging and visual impairment.
Disclosure of Invention
In view of the above problems, the present invention provides an ophthalmic pharmaceutical composition containing ectoin or a derivative thereof (Ectoine). The invention combines the ectoin or the derivative thereof and the cyclosporine, thereby not only improving the treatment effect on the xerophthalmia, but also effectively reducing the side effect and the adverse reaction of a xerophthalmia treatment product which independently takes the cyclosporine as the effective component, and improving the use comfort and the medication compliance of patients.
In a first aspect, the present invention provides an ophthalmic composition comprising: cyclosporin and ectoin or derivatives thereof; the weight ratio of the cyclosporine to the ectoin or the derivative thereof is 1 (1-50).
Further, the weight ratio of the cyclosporine to the ectoin or the derivative thereof is 1 (1.5-6). Optionally, the ectoine derivative is ectoine methyl ester.
The invention also provides a medicament comprising the ophthalmic composition.
Specifically, the medicine also comprises pharmaceutically acceptable auxiliary materials or additives.
Optionally, the medicament is an ophthalmic formulation. The ophthalmic preparation may be a water-soluble eye drop or an oil-in-water emulsion type eye drop.
Further, in the ophthalmic preparation of the present invention, the medicament comprises, in weight percent:
0.025 to 0.05 percent of cyclosporine, 0.075 to 0.15 percent of ectoin or derivatives thereof, 0.4 to 0.8 percent of propylene glycol, 1.0 to 1.5 percent of tyloxapol, 1.0 to 2.0 percent of sodium alginate and the balance of water for injection.
Further, the medicament comprises: 0.05% of cyclosporine, 0.075% of ectoin or derivatives thereof, 0.6% of propylene glycol, 1.2% of tyloxapol, 1.5% of sodium alginate and the balance of water for injection.
Further, the medicament comprises: 0.025 percent of cyclosporine, 0.15 percent of ectoin or derivatives thereof, 0.6 percent of propylene glycol, 1.2 percent of tyloxapol, 1.5 percent of sodium alginate and the balance of water for injection.
The invention also provides the application of the ophthalmic composition in preparing a medicine for treating dry eye. In the above uses, the treatment of xerophthalmia by ectoin or its derivatives can be synergistic with cyclosporin; in addition, the ectoin or the derivative thereof can relieve the intolerable feelings of burning sensation and eye pain, pruritus, stabbing pain and the like of eyes, so that the prepared medicinal preparation can effectively reduce the occurrence of side effects and adverse reactions when treating xerophthalmia, and greatly improves the use comfort and the medication compliance of patients.
The invention also provides a preparation method of the ophthalmic preparation, which comprises the following steps: mixing cyclosporin, propylene glycol and tyloxapol, stirring for dissolving, adding ectoin or its derivative, sodium alginate and water for injection, and stirring for dissolving.
According to the invention, the ectoin or the derivative thereof and the cyclosporine are combined for the first time, so that the treatment effect on the xerophthalmia is improved, the side effects and the adverse reactions of a xerophthalmia treatment product which independently takes the cyclosporine as an effective component are effectively reduced, and the use comfort and the medication compliance of patients are improved.
Detailed Description
As described above, the present invention aims to provide an ophthalmic composition and its use in the preparation of a medicament for dry eye. It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
Description of terms:
cyclosporin (2): white or off-white powder, odorless; it is very soluble in methanol, ethanol or acetonitrile, soluble in ethyl acetate, soluble in acetone or diethyl ether, and hardly soluble in water.
The structural formula is as follows:
ectoin (Ectoine): is a natural amino acid derivative produced by bacteria living under extreme environmental conditions, can be used as an osmoregulation compatible solute, and can stabilize the barrier function of epithelial tissues. The structural formula is as follows:
ectoin derivatives: including salts of ectoin, such as sodium salt, potassium salt, etc. or salts formed with organic bases; ester derivatives of ectoin, such as ectoin, formed by a carboxyl group and an alcohol (which may be, for example, a linear or branched 1-to 3-membered C1-C10 alcohol).
The beauty eyes are the first medicine for treating the dry eye disease from the pathogenesis in the world, and the beauty eyes relieve the ocular inflammatory reaction of a dry eye patient through the cyclosporine anti-inflammatory action, so that the dry eye disease treatment effect is achieved. However, the eye beauty has many side effects, the most common side effect is eye burning sensation, and the incidence rate reaches 17%; in addition, there is a 1% -5% incidence of other adverse reactions.
Therefore, a pharmaceutical preparation containing cyclosporin as an active ingredient has a good therapeutic effect on dry eye, but is not comfortable to use due to side effects and adverse reactions.
After long-time and extensive test screening, the invention unexpectedly discovers that: the combination of the cyclosporine and the ectoine or the derivative thereof has very good effect, and is particularly embodied in that: on the one hand, the ectoin or the derivative thereof and cyclosporine have a synergistic effect on the treatment effect of dry eye; on the other hand, the ectoin or the derivative thereof can effectively relieve the side effects and adverse reactions of eye burning sensation, eye pain, pruritus, stabbing pain and the like caused by the cyclosporine, and greatly improves the use comfort.
Further, the present invention has developed a pharmaceutical preparation for treating dry eye, which comprises cyclosporin and ectoin or a derivative thereof as active ingredients. Because the tear environment of the cornea is aqueous and incompatible with the oil-soluble eye drops, the exertion of the drug effect can be influenced; therefore, the water-soluble eye drop prepared by the method can be fully contacted with and moistened with the cornea, and the drug effect of the eye drop is improved. However, as the cyclosporine is a compound with strong fat solubility, the invention finally leads the cyclosporine to reach the required treatment concentration by the solubilization of propylene glycol and tyloxapol and the combination with a certain amount of ectoin through the screening of a plurality of prescriptions.
The viscosity of the eye drops is properly increased, so that the irritation of the eye drops can be reduced, the retention time of the medicine in eyes can be prolonged, and the curative effect can be improved. Sodium alginate is added into a pharmaceutical preparation, so that on one hand, the viscosity of the eye drops can be increased, and the dynamic viscosity of the eye drops prepared by the method is controlled to be 4.0-6.0cpa.s at 25 ℃ (the inner diameter of a capillary is 0.8 mm); on the other hand, the addition of a proper amount of sodium alginate also contributes to the stability of the eye drop system.
In conclusion, the medicinal preparation for treating xerophthalmia effectively solves the problem that the cyclosporin is insoluble in water, and the cyclosporin can reach the required treatment concentration through solubilization treatment; and the solution still keeps good clarity after accelerated test and long-time standing.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
The test materials used in the examples of the present invention are all conventional in the art and are commercially available or prepared based on the known technical literature. The experimental procedures, for which no detailed conditions are indicated, were carried out according to the usual experimental procedures or according to the instructions recommended by the supplier.
EXAMPLE 1 preparation of ophthalmic drug
Prescription 1: 0.05g of cyclosporine, 0.1g of ectoin, 0.6g of propylene glycol, 1.2g of tyloxapol, 1.5g of sodium alginate and water for injection. The preparation method comprises the following steps:
mixing cyclosporine, propylene glycol and tyloxapol, stirring for dissolving, then adding the ectoin and sodium alginate, finally adding water for injection to 100mL, fully stirring for dissolving, filtering, sterilizing for 30min by flowing steam at 100 ℃, cooling, and carrying out aseptic packaging to obtain the pharmaceutical preparation for treating xerophthalmia.
Prescription 2: 0.05g of cyclosporine, 0.075g of ectoin, 0.4g of propylene glycol, 1.0g of tyloxapol, 1.0g of sodium alginate and water for injection. The preparation method is the same as formula 1.
Prescription 3: 0.025g of cyclosporine, 0.15g of ectoin, 0.8g of propylene glycol, 1.5g of tyloxapol, 2.0g of sodium alginate and water for injection. The preparation method is the same as formula 1.
Prescription 4: 0.05g of cyclosporine, 0.1g of ectoin methyl ester, 0.6g of propylene glycol, 1.2g of tyloxapol, 1.5g of sodium alginate and water for injection. The preparation method is the same as the prescription 1 by replacing ectoin with ectoin methyl ester.
Prescription 5: 0.025g of cyclosporine, 0.125g of ectoin, 0.6g of propylene glycol, 1.2g of tyloxapol, 1.5g of sodium alginate and water for injection. The preparation method is the same as formula 1.
Comparative example 1: 0.05g of cyclosporine, 0.6g of propylene glycol, 1.2g of tyloxapol, 1.5g of sodium alginate and water for injection. The preparation method comprises the following steps:
mixing cyclosporine, propylene glycol and tyloxapol, stirring for dissolving, then adding sodium alginate, finally adding water for injection to 100mL, fully stirring for dissolving, filtering, sterilizing for 30min by flowing steam at 100 ℃, cooling, and carrying out aseptic packaging to obtain the pharmaceutical preparation for treating xerophthalmia.
Comparative example 2: 0.15g of cyclosporine, 0.6g of propylene glycol, 1.2g of tyloxapol, 1.5g of sodium alginate and water for injection. The preparation method is as in comparative example 1.
Comparative example 3: 0.15g of ectoin, 0.6g of propylene glycol, 1.2g of tyloxapol, 1.5g of sodium alginate and water for injection. The preparation method is as in comparative example 1.
Comparative example 4: 0.05g of cyclosporine, 0.1g of ectoin, 0.6g of propylene glycol, 800.15g of tween-sodium, 1.5g of sodium alginate and water for injection. The preparation method comprises the following steps:
mixing cyclosporine, propylene glycol and tween-80, stirring for dissolving, then adding the ectoin, sodium hyaluronate and sorbitol, finally adding water for injection to 100mL, fully stirring for dissolving, filtering, sterilizing for 30min by flowing steam at 100 ℃, cooling, and carrying out aseptic packaging to obtain the pharmaceutical preparation for treating xerophthalmia.
Comparative example 5: hyaluronic acid 0.05g, ectoin 0.1g, propylene glycol 0.6g, tyloxapol 1.2g, sodium alginate 1.5g, and water for injection. The preparation method comprises the following steps:
mixing hyaluronic acid, propylene glycol and tyloxapol, stirring for dissolving, adding ectoin and sodium alginate, finally adding water for injection to 100mL, fully stirring for dissolving, filtering, sterilizing with flowing steam at 100 ℃ for 30min, cooling, and carrying out aseptic packaging to obtain the pharmaceutical preparation for treating xerophthalmia.
Example 2: stability test
1. The test method comprises the following steps:
samples were prepared according to recipes 1-5 and comparative examples 1-5 and stability tests were performed. The test is carried out according to the general rule of IG ophthalmic preparation in appendix of Chinese pharmacopoeia 2015 edition and the requirement of the stability test guiding principle of XIXC bulk drug and pharmaceutical preparation in appendix of Chinese pharmacopoeia 2015 edition, and the samples are examined in an accelerated stability test (6 months).
The measuring index and the method are as follows:
(1) visible foreign matter: the inspection method for foreign matters is in accordance with the appendix IXH of the second part of the pharmacopoeia 2015 year edition.
(2) pH: according to the VIHpH determination method in the appendix of the second part of the pharmacopoeia 2015 year edition; should be 4.5-6.5.
(3) And (3) sterilization: the sterility test method in accordance with the item of IG ophthalmic preparation in the appendix of the second part of the year 2015 edition of Chinese pharmacopoeia shall be met.
(4) Content determination: the cyclosporine content is determined according to VD (vacuum distillation) high performance liquid chromatography which is an appendix of the second part of the Chinese pharmacopoeia 2015 year edition.
(5) Related substances are as follows: according to the appendix of the second part of the Chinese pharmacopoeia 2015 year edition:
filtering (0.45 μm) solution containing 0.5mg per 1ml, and collecting the subsequent filtrate (0.45 μm) of the product as test solution; 2ml of the solution is measured, placed in a 100ml measuring flask, diluted to the mark by adding 50% acetonitrile solution, shaken up and filtered (0.45 mu m), and the subsequent filtrate is taken as a control solution. Octadecylsilane chemically bonded silica is used as a filler, and acetonitrile-water-tert-butyl methyl ether-phosphoric acid (430: 520: 50: 1) is used as a mobile phase; the detection wavelength is 210 nm; and (3) injecting 20 mu l of the control solution into a liquid chromatograph at the column temperature of 70 ℃, adjusting the detection sensitivity to ensure that the peak height of the main component is 20% of the full range, injecting 20 mu l of the test solution into the liquid chromatograph, and recording the chromatogram until the retention time of the main peak is 2 times. If impurity peaks exist in the chromatogram of the test solution, the sum of the peak areas of the impurities is not more than the main peak area (2.0%) of the control solution.
2. And (3) test results:
the results of the accelerated test are shown in Table 1. The method comprises the following specific steps:
table 1: accelerated stability test results
Examination conditions were as follows: the temperature is 40 +/-2 ℃, and the relative humidity is 75% +/-5%
The above results show that: the stability of the whole prescription can be enhanced after the addition of the ectoin in the prescription, and the stability of the eye drops prepared by taking tyloxapol as a solubilizer is found to be stronger than that of eye drops prepared by taking Tween-80 as the solubilizer through screening auxiliary materials. The results show that the raw materials of the eye drops are selected properly, the screened propylene glycol and tyloxapol have good solubilization, and the prepared eye drops have stable systems.
Test example 2: irritation test
1. The test method comprises the following steps:
new Zealand rabbits are used as test subjects and are randomly divided into 10 groups of 5 rabbits, and the age and the weight of the rabbits in each group have no obvious difference.
The sample was added to the left eye of each rabbit in the group at 0.1ml, and the same amount of water for injection was added to the right eye of the rabbit as a control.
After each group is dropped into the test substance, the eyes are closed for 5-10s, 2 times a day, and 7 days continuously. Local responses of the eyes 1h after the first eye drop and before each administration were observed and recorded.
The result judgment standard is carried out according to the eye irritation response judgment standard in the 'guiding principle of preclinical research of new medicine (western medicine)'. The scoring criteria were as follows:
table 3: ocular irritation response scoring criteria
Table 4: evaluation criteria for eye irritation
| Degree of irritation | Integration |
| Has no irritation | 0-3 |
| Mild irritation | 4-8 |
| Moderate irritation | 9-12 |
| Stimulation of intensity | 13-16 |
2. And (3) test results:
the results of the eye irritation test of each treatment group 1h after the first eye drop and 7 days after the first eye drop are shown in Table 5.
Table 5: eye irritation test results
The results show that: in the above formulas, compared with the comparative examples, ectoin or its derivative was effective in reducing the irritativeness of cyclosporin to rabbit eyes, and the comparison between the formula 1 group and the formula 4 group revealed that ectoin had a stronger effect than methyl ectoin. Comparative example 3 shows that ectoin alone is non-irritating to the eyes.
Test example 3: examination of therapeutic Effect on Dry eye
1. The test method comprises the following steps:
1.1 animal grouping and model building:
50 healthy New Zealand white rabbits, which are half male and female, weigh 1.8-2.5 kg, and the left eye is a blank control group and the right eye is a modeling eye. After molding, the samples were randomly divided into 10 groups, a model control group, a prescription 1-5 group, and a comparative example 1-5 group. The molding method comprises the following steps: each new zealand rabbit was anaesthetised topically with 3% pentobarbital intravenous anaesthesia and 2% lidocaine as eye drops. Then, 1 piece of filter paper strip with the size of about 10mm multiplied by 5mm and 1mol/L of NaOH solution is placed on the bulbar conjunctiva which is about 2mm away from the upper part of the corneal limbus of the rabbit, and the conjunctival sac is repeatedly washed by 100mL of physiological saline immediately after 90 s.
1.2 methods and dosages of administration:
from day 1 after molding, each group was administered with the corresponding drug for treatment. Both the blank control group and the model control group were administered with 100. mu.l of physiological saline, and the prescription 1-5 groups and comparative examples 1-5 groups were administered with the eye drops prepared according to the prescription 1-5 and comparative examples 1-5, respectively, in a dose volume of 100. mu.l, 2 times per day at an interval of about 12h, and were administered continuously for 10 days.
1.3 observation indexes and detection methods:
conjunctival congestion, corneal transparency, neovascularization, and corneal epithelium healing were observed under slit lamps on days 1, 5, and 10 after administration, and Schirmer i test and But test were performed.
1.3.1Schirmer I test
And 3-4 h after administration, carrying out backlight inspection on eyes of the New Zealand rabbits in an indoor environment with medium brightness and humidity. Under a slit lamp microscope, the reverse folding end of the phenol red cotton thread is lightly placed at the fornix part at the junction of the middle and rear parts 1/3 of the lower eyelid by using a pair of micro-tweezers, and the phenol red cotton thread is taken out after 1min and the wet length of the phenol red cotton thread is measured.
1.3.2But test
Firstly dripping 2 mul of 1% fluorescein sodium into the conjunctival sac of the lower eyelid, manually blinking for a plurality of times with constant force, then opening the two eyes of the rabbit with constant force, observing the cornea with cobalt blue light of a slit lamp microscope, and obtaining the time when the 1 st black spot appears on the green film of the cornea, namely tear break-up time (burst). And (3) repeating the measurement 3 times when the normal But abnormal bus is 10-15 seconds and less than 10 seconds, and taking an average value.
2. And (3) test results:
the results of the Schirmer I test at different times for each group are shown in Table 6, and the results of the But test are shown in Table 7.
Table 6: schirmer I test results
The above experiments show that the therapeutic effect of the combination of ectoin and derivatives thereof and cyclosporin is significantly better than that of cyclosporin alone. The results of the formulas 1 to 5 and the comparative examples 1 to 3 show that ectoin does not affect the therapeutic effect of cyclosporin on dry eye, has statistical significance, and that ectoin is used more effectively than its derivatives.
In addition, the difference between the curative effects of the prescriptions 1 and 5 is not large, which shows that the dosage of the ciclosporin can be reduced by increasing the dosage of the ectoin, and further shows that the ectoin can enhance the curative effect of the ciclosporin on the dry eye. In contrast, comparative example 3 shows that ectoin alone has almost no therapeutic effect on dry eye.
Table 7: but test
The But experiment result also shows that the treatment effect of the combination of the ectoin and the derivative thereof and the cyclosporine is obviously better than that of the cyclosporine alone. The dosage of the ciclosporin can be reduced by increasing the dosage of the ectoin, and the treatment effect of the ciclosporin on the xerophthalmia can be further improved by the ectoin.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (10)
1. An ophthalmic composition, comprising:
cyclosporin and ectoin or derivatives thereof; the weight ratio of the cyclosporine to the ectoin or the derivative thereof is 1 (1-50).
2. The ophthalmic composition of claim 1, wherein the weight ratio of the cyclosporin to the ectoin or the derivative thereof is 1 (1.5-6).
3. The ophthalmic composition of claim 1 wherein the ectoine derivative comprises methyl ectoine.
4. A medicament comprising a composition as claimed in any one of claims 1 to 3.
5. The medicament of claim 4, wherein the medicament comprises an ophthalmic formulation.
6. The medicament of claim 5, wherein the medicament comprises, in weight percent:
0.025 to 0.05 percent of cyclosporine, 0.075 to 0.15 percent of ectoin or derivatives thereof, 0.4 to 0.8 percent of propylene glycol, 1.0 to 1.5 percent of tyloxapol, 1.0 to 2.0 percent of sodium alginate and water for injection.
7. The medicament of claim 6, wherein the medicament comprises:
0.025% of cyclosporine, 0.15% of ectoin or derivatives thereof, 0.6% of propylene glycol, 1.2% of tyloxapol, 1.5% of sodium alginate and water for injection.
8. The medicament of claim 6, wherein the medicament comprises:
0.05% of cyclosporine, 0.075% of ectoin or derivatives thereof, 0.6% of propylene glycol, 1.2% of tyloxapol, 1.5% of sodium alginate and water for injection.
9. Use of the ophthalmic composition of any one of claims 1-3 for the manufacture of a medicament for dry eye.
10. A process for the preparation of a medicament according to claim 4, said medicament being selected from ophthalmic formulations, said process comprising the steps of:
mixing cyclosporin, propylene glycol and tyloxapol, stirring for dissolving, adding ectoin or its derivative, sodium alginate and water for injection, and stirring for dissolving.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010544698.9A CN111905094B (en) | 2020-06-15 | 2020-06-15 | Ophthalmic composition and application thereof in preparation of medicine for treating xerophthalmia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010544698.9A CN111905094B (en) | 2020-06-15 | 2020-06-15 | Ophthalmic composition and application thereof in preparation of medicine for treating xerophthalmia |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111905094A true CN111905094A (en) | 2020-11-10 |
| CN111905094B CN111905094B (en) | 2022-08-09 |
Family
ID=73237866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010544698.9A Active CN111905094B (en) | 2020-06-15 | 2020-06-15 | Ophthalmic composition and application thereof in preparation of medicine for treating xerophthalmia |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111905094B (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101491525A (en) * | 2009-03-03 | 2009-07-29 | 山东大学 | Use of tetrahydropyridines in preparing medicine for treating oerophthalma |
| US20110027327A1 (en) * | 2007-10-02 | 2011-02-03 | Kuhs Gmbh | Cosmetic or pharmaceutical composition for topical application |
| KR20120022574A (en) * | 2010-07-30 | 2012-03-12 | 주식회사종근당 | Ophthalmic formulation containing cyclosporine a |
| CN103656617A (en) * | 2012-09-26 | 2014-03-26 | 沈阳兴齐眼药股份有限公司 | Preparation method of ciclosporin ophthalmic solution |
| CN103735495A (en) * | 2014-01-23 | 2014-04-23 | 兆科药业（合肥）有限公司 | Ciclosporin eye gel and preparation method thereof |
| US20150010634A1 (en) * | 2011-10-12 | 2015-01-08 | Ascendis Pharma Ophthamology Division A/S | Prevention and treatment of ocular conditions |
| CN107998399A (en) * | 2017-12-22 | 2018-05-08 | 北京诺康达医药科技有限公司 | A kind of cyclosporine compound eye drops and preparation method thereof |
| CN108778250A (en) * | 2016-03-07 | 2018-11-09 | 乌尔萨法姆药物有限责任公司 | Ophthalmic composition |
| EP3412276A2 (en) * | 2017-06-09 | 2018-12-12 | Omnivision GmbH | Composition for the treatment of dry eye |
| CN110237233A (en) * | 2019-07-30 | 2019-09-17 | 沈阳兴齐眼药股份有限公司 | A kind of medical composite for eye containing cyclosporine, preparation method and the usage |
-
2020
- 2020-06-15 CN CN202010544698.9A patent/CN111905094B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110027327A1 (en) * | 2007-10-02 | 2011-02-03 | Kuhs Gmbh | Cosmetic or pharmaceutical composition for topical application |
| CN101491525A (en) * | 2009-03-03 | 2009-07-29 | 山东大学 | Use of tetrahydropyridines in preparing medicine for treating oerophthalma |
| KR20120022574A (en) * | 2010-07-30 | 2012-03-12 | 주식회사종근당 | Ophthalmic formulation containing cyclosporine a |
| US20150010634A1 (en) * | 2011-10-12 | 2015-01-08 | Ascendis Pharma Ophthamology Division A/S | Prevention and treatment of ocular conditions |
| CN103656617A (en) * | 2012-09-26 | 2014-03-26 | 沈阳兴齐眼药股份有限公司 | Preparation method of ciclosporin ophthalmic solution |
| CN103735495A (en) * | 2014-01-23 | 2014-04-23 | 兆科药业（合肥）有限公司 | Ciclosporin eye gel and preparation method thereof |
| CN108778250A (en) * | 2016-03-07 | 2018-11-09 | 乌尔萨法姆药物有限责任公司 | Ophthalmic composition |
| EP3412276A2 (en) * | 2017-06-09 | 2018-12-12 | Omnivision GmbH | Composition for the treatment of dry eye |
| CN107998399A (en) * | 2017-12-22 | 2018-05-08 | 北京诺康达医药科技有限公司 | A kind of cyclosporine compound eye drops and preparation method thereof |
| CN110237233A (en) * | 2019-07-30 | 2019-09-17 | 沈阳兴齐眼药股份有限公司 | A kind of medical composite for eye containing cyclosporine, preparation method and the usage |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111905094B (en) | 2022-08-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2175858B1 (en) | Pharmaceutical compositions and methods of treating dry eye disorders | |
| Qi et al. | In vitro evaluation of enhancing effect of borneol on transcorneal permeation of compounds with different hydrophilicities and molecular sizes | |
| CN110237233B (en) | Ophthalmic pharmaceutical composition containing cyclosporine, preparation method and application thereof | |
| DE3310079A1 (en) | TOPICAL OPHTHALMIC MEDICINAL PRODUCTS | |
| AU2020220957B2 (en) | Formulations of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile | |
| EP2506843A2 (en) | Treating xerophthalmia with compounds increasing meibomian gland secretion | |
| DE69208941T2 (en) | Extended-release eye preparations | |
| US20240342174A1 (en) | Methods for treating ocular surface pain | |
| CN111905094B (en) | Ophthalmic composition and application thereof in preparation of medicine for treating xerophthalmia | |
| CN110812323B (en) | Ophthalmic composition, preparation method and application thereof | |
| US20210401919A1 (en) | Ophthalmic Compositions | |
| WO2001028553A1 (en) | Rivastigmine for the treatment of ocular disorders | |
| CN111437252B (en) | Ophthalmic preparation containing erigeron breviscapus extract, preparation method and application | |
| TW201904562A (en) | Oil-in-water nanoemulsion composition of beclomethasone | |
| EP4282401A1 (en) | Ophthalmic preparation administered by eye drops and used for preventing and treating dry macular degeneration and retinal light damage | |
| CN112870216A (en) | Pharmaceutical composition, preparation and application | |
| CN112294761A (en) | Ophthalmic micelle preparation of insoluble drug | |
| CN116327873A (en) | Application of zedoary turmeric oil in preparing medicament for treating xerophthalmia | |
| CN114099505A (en) | Ophthalmic composition and preparation method and application thereof | |
| KR20240032950A (en) | Composition containing loxoprofen sodium | |
| CN117599108A (en) | Long-acting ophthalmic preparation for improving eyelid inflammation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230607 Address after: Tianchen Avenue, Ji'nan hi tech Development Zone of Shandong Province, No. 678 250101 Patentee after: BLOOMAGE BIOTECH Co.,Ltd. Address before: Tianchen Avenue, Ji'nan hi tech Development Zone of Shandong Province, No. 678 250101 Patentee before: BLOOMAGE BIOTECH Co.,Ltd. Patentee before: SHANDONG BLOOMAGE HYINC BIOPHARM Corp.,Ltd. |